We propose to use the tools of structural biology to develop a perspective that will lead to fundamental understanding of the structures and interactions of the proteins of the human immunodeficiency virus (HIV). The information will be used as the basis for the chemical design of agents that may be pharmacologically active. Our approach is conceptually straightforward: a) We will produce proteins by expression in E. coli and cultured cells, and peptides by solid phase synthesis. b) We will carry out biochemical analysis of catalytic activities, binding characteristics and other properties. c) We will study the structures and interactions of the molecules using physical methods including x-ray crystallography, neutron diffraction, NMR, and optical spectroscopy. Some strategies of chemical modification will be used as well. d) We will develop a conceptual framework for the study of electrostatic and steric interactions of molecules in the aqueous phase and in the hydrophobic region of lipid bilayer envelopes. Thus, we will have the materials methods, and concepts needed to explore the fundamental structural biology of the HIV proteins and to move toward the use of that understanding in the design of pharmacologically active agents.